The PTH/PTHrP receptor (PPR) mediates the biological actions of two peptide hormones, PTH and PTH-related peptide (PTHrP). PTH is the major regulator of mammalian mineral ion homeostasis. PTHrP and the common PPR are both crucial for normal development, since the disruption of either gene in mice results in lethal phenotypes with widespread abnormalities of endochondral bone formation. These "knockout" studies indicated furthermore that the common PPR is essential for mediating the functions of PTH and PTHrP, and that no other receptor can serve as a substitute. However, a novel, PTH-specific receptor (PTH2R) with significant amino acid sequence homology to the PPR was isolated from mammals, but its biological importance is not yet known. Interestingly, cDNAs encoding fish PTH2R homologs were recently isolated also from catfish and zebrafish cDNA libraries. If these novel receptors are activated only by PTH, as the mammalian PTH2R homolog, these findings suggest that a PTH-like molecule exists also in vertebrate species that do not have parathyroid glands and that PTH expression occurs in species lacking distinct parathyroid glands. In the current proposal, I will therefore study the coevolution and function of two closely related G protein-coupled PTH-/PTHrP-receptors and their two distinct ligands. The resulting findings are expected to provide evidence for possible function(s) of both ligands and both receptors in nonmammalian vertebrates, and may provide further clues for biological role(s) in mammals that are distinct from those required for the control of mineral ion homeostasis.